Both isoforms of the hepatitis delta antigen (HDAg) of hepatitis delta virus (HDV) are highly associated with virus proliferation and may act as co-activators of cellular gene expression. Human hepatocellular carcinoma (HCC) cell line Huh7, which stably expresses HDAgs, was differentially screened and the results showed that clusterin gene expression was enhanced. The mechanisms for HDAg-mediated clusterin gene upregulation were investigated. Expression of HDAgs was associated with enhanced histone H3 acetylation within the clusterin promoter in a chromatin immunoprecipitation assay. Transient transfection of HDAg-expressing plasmids into Huh7 cells also enhanced clusterin expression and histone acetylation. Furthermore, HDV replication was associated with histone hyperacetylation and clusterin induction. The effect of increased clusterin expression was determined by a chemosensitivity assay with adriamycin treatment. These data indicated that HDV-induced clusterin protein increases cell survival potential. Thus, it is possible that epigenetic regulation by HDV contributes to a pathological outcome of hepatitis D/hepatitis B viral hepatitis and HCC.